Process for preparing steroidal hormones



- oidal saposenins Patented Aug. 28, 1945 UNITED I STATES PATENT OFFI PROCESS FOR PREPARING STEROIDAL HORMONES Parke, Davis & Compa poration of Michigan N Drawing. Application Detroit, and Eldon M. oods, Mich., assignors to ny, Detroit, Mich., a cor- July 5, 1944,

Serial No. 543,612

This invention relates to a new process for preparing ZO-keto-pregnane compounds from steror derivatives thereof. particularly, it relates to the conversion of genin derivatives having the structure at ring D of the steroid nucleus into compounds having the structure (b) R: CO0H tains as a product of the reaction a compound having the structure (II) carrying hydrogen at position 16 in place of the acyloxy group,

Suitable hydrogenolytic agents for carrying out this a. mild reducing action.

The utility of this invention lies in the fact that, by a single step, compounds of type (I) may 11 Claims. (o1. zso ssmi be converted to type (II), whereas it has been the practice to. first hydrolyze a type (I) commight also be susceptible to reductio I sodium carbonate or The practice of the invention may be illustrated purposes of illustration only, and the scope of the invention is not necessarily limited thereto.

Example 1 A solution of 25 grams of pseudo-diosgenin diacetate in 500 cc. of glacial acetic acid is allowed to react at room temperature (between 20 and a solution of 125 gms. of chromium trioxide in 125 cc. of acetic acid for a period of 1 hours. At the end of this period, three grams of zinc bromide and thirty dust are added to the solution, the temperature rising to about C. and the solution heated on the steam bath for 1 hour additional. At the end of this time, the solid excess zinc is filtered from the solution, the clear filtrate evaporated essen- I other dilute alkali. neutral ether solution is dried and then evaporated to dryness. The residue may be crystallized from acetone or methanol to give essentially pure M-pregnen-BpolQO-one acetate, M. P. 147-9" 0.

Example 2 Pseudo-diosgenin diacetate is oxidized in the same manner as in Example 1. The excess oxidizing agent is destroyed by sodium sulfit, the reaction mixture diluted with three volumes of water and extracted with ether.

The ether extract is washed free of salts and of acids with water and with dilute alkali solution and the dried, neutral ether solution evaporated to dryness. The residue, ring D, where the acyl group is the acetate radical, is dissolved in 600 cc. of ethanol. 300 cc. of a 10% solution of potassium bicarbonate in water is then added, as well as 25 gms. of powdered zinc. The mixture is refluxed move excess zinc, the with mineral acid and umes with water.

filtrate made faintly acid finally diluted to four vol- The precipitated solid is colhaving structure (Ia) at.

for 3 hours, filtered to relected and crystallized to yield essentially pure A -oregnen-3pol-20-one, M. P. 191 C.

Eaample 3 from suitable solvent, such aqueous acetone or aqueous methanol, gives crystalline progesterone, M. P. 128 C.

The transformations of this example may be illustrated as follows:

CHI =0 Progesterone Example 4 Ten grams of dissolved in 200 cc. of glacial acetic acid and to the solution there is added 23.3 cc. of a 1 molar solution of bromine in acetic acid. To this solution is now added a solution of ten grams of chromic oxide in. 100 cc. of 60% acetic acid, maintaining the temperature below 40 C. After 1 /2 hours oxidation, ten grams of added to the solution and the mixture heated with stirring on the steam bath for 1 hour. The excess zinc is filtered from the solution and the filtrate worked up as was done with the filtrate from excess zinc in Example 1. Evaporation of the resulting neutral ether solution (after drying) leaves a gummy residue which on crystalbath'ior 1 hour, 1 in Example 1. Evapora tion of the dry, neutral ether solution resulting-i gives an oily residue which on crystallization as ether, ligroin,

. and conditions at rins D which il-tokappogenin (0.0233 moles) is also dust is lization from a suitable solvent gives crystalline progesterone, M. P. 128 C.

The transformations 0! this example may be illustrated as follows:

Kn genln B ar -o-oo-crnomon-ooon H.

'Zn+H0Ao .mbrommmoamdamumwm hydroiemiyslll amples and numerous variations in the materials will. occur to those skilled in the art.

Although the invention in its broader features is applicable to' 'anysteroidhavinz structure (I) I be converted to structure (11) the preferred compounds which we submit to mild hydrogenolysis are those of most value as .sex hormone intermediates and havlnz one o! the following structures in rings A and B,

and

no A n 2,383,472 3 where R is hydrogen or organic carboxylic acid into a, steroid derivative having at ring D the acyl group, such as acetyi, benzoyl, etc. structure,

What we claim as our invention is: CHI 7 1. The process for converting a steroid ester having at ring D the structure,

3' {I =0 I 'I EH3 OH- in v g 10 Q +0 C-p-o-cmQm-CH-R D g B said ester and also its derivative having in rings 4 A and Bone oi the structures, a

. H; Y I CH:

. r into a steroid derivative having at ring D the structure, 'A B r V f CHI H CH] C/ \CH| /ll-3H| H 120% B which comprises treating said ester with a metal H of the class consisting of zinc, magnesium and which comprises treating said ester with a metal aluminum in the presence of a compound of the of the class consisting of zinc, magnesium and class consisting of weakly alkaline and weakly al m n in the p s n o a mp nd f th acidic compounds capable of liberating nascent hydrogen from said metal, R of the formula being a radical of the class consisting of CHzOAcyl and COOH.

2. The process for converting a steroid ester having at ring D the structure, 1

=0 Cg: -c C0-CCHiCHr-CHR l D in i H.

into a steroid derivative having at ring D the structure,

caving at. ring D the structure,

CHI

=0 on. on I C C-o-(.;:OH:CH2CHR l D l H 4) Hi 4. The pigohess for having at ring D the converting a steroid ester structure,

said ester and also its derivative having in rings A and B one of the structures, I OH:

A B o and .'75 which comprises treating said ester with a metal of the class consisting of zinc, magnesium and aluminum in the presence of a lower fatty acid capable of liberating nascent hydrogen from said metal, R of the'formula being a radical of the class consisting of -CHzOAcyl and 5. Process for replacing by hydrogen the -16 ester group,

-OCO-CH1OH -OH-R of a 0-16 ester of a compound of the class consisting of 16-hydroxy-A-pregnenone-3;16-hydroxy-M-pregnenol-B and C-3 carboxylic acid esters of said l6-hydroxy-A -pregnenol-3, whichcomprises treating said 0-16 ester with a metal of the class consisting of zinc, magnesium and aluminum in the presence of a compound of the class consisting of weakly alkaline and weakly acidic compounds capable of liberating nascent hydrogen from said metal, R of the 0-16 ester grou being a radical of the class consisting of -CHaOAcyl and -COOH.

6. Process for replacing by hydrogen the 0-16 ester group of a 16-hydroxy-A -pregnenone-3 ester having at ring D the structure,

whichcomprises treating said 0-16 ester with a metal of the class consisting of zinc, magnesium and aluminum in the presence of a compound of the class consisting of weakly alkaline and weakly acidic compounds capable of liberating nascent hydrogen from said metal, R of the C-16 ester group being a radical of the class consisting of -CHzOAcyl and--COOH.

'1. Process for replacing by hydrogen the C-16 ester group of a lti-hydroxy-A-pregnenone-3 ester having at ring D the structure,

which comprises treating said ester with a metal of the class consisting of zinc, magnesium and aluminum in the presence of a lower fatty acid capable of liberating nascent hydrogen from said metal, R of the formula being a radical of the class consisting of CI-Iz'OAcyl and -COOH.

8. Process for obtaining progesterone from a C-16 ester of '16-hydroxy-A -pregnenone-3 of formula CHI 5 on. on i X:-c-ca,cm-ca-coon H0 which comprises treating said ester with zinc and lower fatty acid.

9. Process for obtaining progesterone which comprises treating an ester of i6-hydroxy-5,6- dibromo-pregnandione-3,20 of formula,

with zinc and lower fatty acid.

10. Process for obtaining progesterone from a 0-16 ester of 18-hydroxy-A -pregnenone-3 of formula CH8 CH o-c-cn CH cn-coon Vi which comprises treating said ester with zinc and acetic acid.

11. Process for obtaining progesterone which comprises treating an ester of 16-hydroxy-5,6-

ELDON M. JONES. 

